Info on fentanyl

Page 2 of autopsy report

No life-threatening injuries identified

Fentanyl 11 ng/mL

Norfentanyl 5.6 ng/mL

Morphine - Free 86 ng/mL

Page 17

In fatalities from fentanyl, blood concentrations are variable and have been reported as low as 3 ng/mL.

Apparently fentanyl gets metabolized into the inactive norfentanyl. So I think this indicates an upper level dose which is the sum of these two, 16.6 ng/mL.

According to this, the typical therapeutic concentration is 0.63 to 2 ng/mL.

A 2017 case report published in Academic Emergency Medicine detailed an outbreak of fentanyl overdoses in Northern California.

...

All 18 patients tested positive for the drug. The mean serum fentanyl concentration of 52.9 ng/mL was considerably higher than therapeutic concentrations ranging from 0.63 to 2 ng/mL.

Postmortem Toxicology Findings of Acetyl Fentanyl, Fentanyl, and Morphine in Heroin Fatalities in Tampa, Florida

In the heroin cases with fentanyl present (n=7), the average free morphine concentration was 0.040 mg/L, the average total morphine concentration was 0.080 mg/L, and the average fentanyl concentration was 0.012 mg/L.

0.040 mg/L free morphine is the same as 40 ng/mL.

0.012 mg/L of fentanyl is the same as 12 ng/mL.

One thing that happens in drug addiction is that your receptors increase in number (upregulate) and then decrease in number (downregulate) when people stop for a while. With prolonged drug use, people need higher doses to saturate their receptors in order to get an effect.

Just some information about how overdosing and receptor sensitivity works, if you're unfamiliar.

Desensitization

Desensitization

Desensitization refers to a reduced response to an agonist drug due to over activation of a receptor (high doses, prolonged exposure to agonist). There is a number of mechanisms of desensitization including: loss of receptor function through a decrease in receptor-coupled signaling components (e.g., G-proteins). Receptor desensitization may occur in the absence of significant changes in the number of receptors.

Downregulation

Downregulation specifically refers to a reduction in the total number of receptors available to be stimulated due to prolonged receptor activation (e.g. by chronic treatment with a pharmacological agonist drug or prolonged inhibition of metabolism of a neurotransmitter). This reduction in receptors in turn will decrease the cell’s sensitivity to an agonist or drug. Downregulation occurs through endocytosis. Internalized receptors may either be degraded in the lysosomes or recycled back to the membrane surface later.

What happens when people return to doing drugs after time off, is that they've become re-sensitized, i.e. they can get a similar effect from a lower dose that previously required a higher dose because their receptors returned to normal. Then when they ingest a dose that they previously required to get an effect (a higher than normal dose), but because they're more sensitive, they end up overdosing.